In the paper by Ishida et al. in this issue of Cancer Cell, the authors report the results of targeted inactivation of a Rap1-specific GTPase-activating protein (GAP) gene, called SPA-1, in mice. Rap1 hyperactivation was observed in hematopoietic cells, which led over time to features associated with symptoms typical of human myeloid dyslastic and myeloid proliferative diseases. The authors present additional data showing that the level of Rap1 activation is important for regulating myelopoiesis and that, in the right context, can deliver an oncogenic signal.